A monoclinic polymorph of chlorothiazide

Accessible from basic aqueous solutions, a new monoclinic polymorph of the diuretic chlorothiazide is described.


Chemical context
Chlorothiazide (CTZ) is an Active Pharmaceutical Ingredient (API) used as a diuretic and as an antihypertensive drug (Martins et al., 2022;Steuber et al., 2020).It has been widely used as a model API in crystallization studies, for instance in screens for solvate and cocrystal forms (Johnston et al., 2011;Aljohani et al., 2017;Teng et al., 2020).Crystal structures of Na and K salt forms have also been reported (Paluch et al., 2010(Paluch et al., , 2011)).Finally, CTZ has also been used as a model API in various technique development studies, techniques such as structure solution from powder diffraction (Shankland et al., 1997), crystal-structure prediction (Johnston et al., 2011) and high-pressure structural studies of molecular materials (Oswald et al., 2010).Despite this attention, only one crystalline polymorph of CTZ has been reported as being accessible under ambient conditions.This is Form I CTZ.Indeed Johnston and co-workers screened the crystallization of CTZ from 67 solvents, each under diverse experimental conditions, and only Form I CTZ and solvates of CTZ were identified.Combining these results with a crystal-structure prediction study gave the suggestion that 'the appearance of an alternative polymorph of CTZ from standard solution crystallizations is unlikely' (Johnston et al., 2011).
Form I is a triclinic, space group P1, structure that was initially reported from a powder diffraction study (Shankland et al., 1997) with a single-crystal diffraction determination available from Leech et al. (2008).A second closely related polymorph, Form II, was reported in 2010 by Oswald and coworkers.However, this was formed at high pressure (4.4 GPa) by compressing Form I.The transformation is reversible at lower pressures and thus Form II does not persist under standard conditions.Like Form I, Form II is also a triclinic, space group P1, structure.Using procedures similar to those outlined by Paluch et al. (2010) to isolate salt forms of CTZ, we crystallized CTZ from water multiple times and often under basic conditions.Despite the earlier predictions, several of these crystallizations produced crystals of a new monoclinic, space group P2 1 , form of CTZ suitable for single-crystal X-ray diffraction studies.The structure of this Form III of CTZ is reported herein and is compared to those of its polymorphs.

Structural commentary
Form III CTZ was originally crystallized from aqueous solution in the presence of Ba(OH) 2 , see the Synthesis and crystallization section for details.It was also prepared by similar experiments using either Mg(OH) 2 or a mix of NaOH and SrCl 2 , in each case the phase was confirmed by X-ray diffraction and by FTIR.See the supporting information for the IR spectra of Forms I and III.The identification of a new polymorph of CTZ is interesting as the phase space of this API has been widely studied.For instance, Johnston et al. (2011) performed a crystallization screen using over 400 crystallization procedures and 67 solvents that produced only Form I CTZ and solvate structures.This study showed that, despite CTZ being very sparingly soluble in water (Merk, 1996), Form I of CTZ could be isolated from aqueous solutions.In our hands, water slurries of CTZ gave only Form I, as shown by IR.The driver for the formation of the new polymorph is thus not using water as the solvent.Relevant known factors that can give polymorphic forms of organic materials are the presence of metal ions (for instance paracetamol, Kennedy et al., 2018), and change in pH (for instance glycine, Tang et al., 2017).To test this we repeated the preparation using ammonia rather than Ba(OH) 2 .This metal-ion-free crystallization also produced Form III CTZ, as identified by IR.The driver to Form III generation thus may be the change to higher pH, which here is associated with a much higher aqueous solubility of CTZ.
The molecular structure of CTZ in Form III is show in Fig. 1.The secondary amine proton is found bound to N2.This is the commonly described tautomer of CTZ, with the alternate protonation of the sulfonamide nitrogen (here N1) only described in structures of salt forms (Paluch et al., 2010(Paluch et al., , 2011)).The molecular conformation of CTZ in Form III is similar to that found in Form I, with the ring S atom displaced out of the ring plane in the opposite direction to the S-NH 2 bond vector.However, there are small differences.The magnitude of the C7-C8-S2-N3 torsion angle is 106.7 (3) � in Form III as compared to 109.1 � in Form I and the out-of-ring-plane displacement of the S atom is greater in Form III (0.422 versus 0.264 A ˚). Interestingly, this latter distortion is similar to that seen in the high-pressure Form II, where the out-of-plane distortion increases with increasing pressure to a maximum of 0.473 A ˚at 5.9 GPa.

Supramolecular features
Form III CTZ forms four independent classical hydrogen bonds all of the N-H� � �O type, see Table 1.The ring N-H forms a hydrogen bond to an O atom of a neighbouring ring SO 2 group, whilst the amine H atoms of the SO 2 NH 2 groups all interact with O atoms of neighbouring SO 2 NH 2 groups.In the case of atom H3N, this is a bifurcated interaction to two molecules.This leaves atom O2 of the ring SO 2 and all the N atoms unused as hydrogen-bond acceptors.This differs fundamentally from Form I CTZ.There, in addition to three N-H� � �O hydrogen bonds, there are also two N-H� � �N interactions.Thus it is an O atom of each of the SO 2 groups that does not act as an acceptor.The hydrogen bonding of Form III thus consists of only head-to-head and tail-to-tail interactions (where the head group is SO 2 NH 2 and the tail group is the C 3 N 2 S ring), whilst in Form I most of the interactions are head-to-tail.The resulting differences in packing can be seen in Figs. 2 and 3.In Form III (Fig. 2), the mix of head-to-head and tail-to-tail interactions gives a packing motif with C9-Cl1 vectors pointing both left and right.However, in Form I (Fig. 3) all equivalent C-Cl vectors are to the right, as would be expected for a space group that features only translational symmetry.
The program CrystalExplorer (Spackman et al., 2021) was used to investigate the intermolecular interactions of Forms I and III.Hirshfeld surfaces, fingerprint plots and interaction energy details are given in the supporting information.The three strongest intermolecular interaction types were found to be common to both polymorphs.In each case, the strongest pair interaction was that based around the ring-to-ring  N-H� � �O hydrogen bond shown in Fig. 4.This had an energy of À 58.5 kJ mol À 1 for Form III and À 41.1 kJ mol À 1 for Form I. Perhaps surprisingly, for each polymorph it is the nonclassical C-H� � �O hydrogen-bond interaction shown in Fig. 5 that is the next strongest, with energy values of À 30.4 and À 40.8 kJ mol À 1 for Forms III and I, respectively.The third common intermolecular motif is the hydrogen-bondsupported stack motif, shown in Fig. 6, that corresponds to translation along the crystallographic a axis.This has energy values of À 24.1 and À 28.6 kJ mol À 1 for Forms III and I, respectively.Totalling all the pairwise interaction energies gives À 296.0 kJ mol À 1 for Form III and À 308.8 kJ mol À 1 for Form I.This suggests that triclinic Form I is thermodynamically  For both polymorphs I and III, this N-H� � �O interaction type forms the strongest bond between molecular pairs.The motif is shown here for Form III, but a similar motif is also found in Form I.  C-H� � �O interaction motif.Shown here for Form III, but a similar motif is also found in Form I.

Figure 6
Hydrogen-bond-supported stacking motif corresponding to a translation along the crystallographic a axis.Shown here for Form III, but a similar motif is also found in Form I. favoured over the newly described monoclinic Form III.This assignment is supported by both the melting point data (see Synthesis and crystallization) and by slurry experiments.After 10 days with cyclic heating to 350 K, a sample of Form III partially dissolved in water had transformed to Form I as shown by FTIR.A similar experiment using Form I material gave no transformation.

Database survey
A search of the Cambridge Structural Database (CSD, version 5.45 updates to March 2024; Groom et al., 2016) found two polymorphic forms of CTZ, the ambient condition Form I (Leech et al., 2008) and the high-pressure only Form II (Oswald et al., 2010).The structures of many solvate and cocrystal forms of CTZ have also been reported (for examples, see: Johnston et al., 2011;Aljohani et al., 2017;Teng et al., 2020).Johnston et al. also list approximately 135 predicted crystal structures of CTZ that have lattice energies that lie within 15 kJ mol À 1 of their global minimum.Of these, the unit cell of af74 is perhaps closest to that found for Form III (predicted P2 1 , a, b, c = 4.9301, 6.7048, 17.268A ˚, � = 93.694� ).This structure had a predicted lattice energy that was approximately 8.7 kJ mol À 1 less stable than that of their predicted Form I structure.

Synthesis and crystallization
CTZ Form I was purchased from Thermo Scientific.0.1 g (3.4 mmol) of Form I CTZ formed a slurry with 15 cm 3 of deionized water.An equimolar amount of Ba(OH) 2 •8H 2 O was added and the slurry clarified to a solution.After filtering, this solution was left to evaporate for 5 days after which point colourless crystals of Form III CTZ had formed.Similar experiments using Mg(OH) 2 or a mix of NaOH and SrCl 2 in place of Ba(OH) 2 also gave crystals of Form III CTZ.A final slurry of 0.1 g of Form I CTZ in 15 cm 3 of deionized water had 35% aqueous ammonia solution added to it dropwise until the solution clarified.After evaporation for 7 days, a white powder formed that was shown to be Form III CTZ by FTIR.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. H atoms bound to C atoms were placed in expected geometric positions and treated in riding modes with C-H = 0.95 A ˚and with U iso (H) = 1.2U eq (C).H atoms bound to N were refined isotropically with N-H restrained to 0.88 (1) A ˚.The structure was refined as a twocomponent inversion twin.

Figure 1
Figure 1Molecular structure of CTZ Form III with non-H atoms shown as 50% probability ellipsoids.Hydrogen atoms are shown as small spheres of arbitrary size.

Figure 3
Figure 3 Packing diagram of Form I CTZ with a view along the crystallagraphic aaxis direction.Diagram constructed using the CIF file available from Leech et al. (2008).

Figure 2
Figure 2Packing diagram of Form III CTZ with a view along the crystallagraphic a-axis direction.

Table 2
Experimental details.